Effect of gemigliptin on cardiac ischemia/reperfusion and spontaneous hypertensive rat models

Diabetes is associated with an increased risk of cardiovascular complications. Dipeptidyl peptidase-4 (DPP-IV) inhibitors are used clinically to reduce high blood glucose levels as an antidiabetic agent. However, the effect of the DPP-IV inhibitor gemigliptin on ischemia/reperfusion (I/R)-induced myocardial injury and hypertension is unknown. In this study, we assessed the effects and mechanisms of gemigliptin in rat models of myocardial I/R injury and spontaneous hypertension. Gemigliptin (20 and 100 mg/kg/d) or vehicle was administered intragastrically to Sprague-Dawley rats for 4 weeks before induction of I/R injury. Gemigliptin exerted a preventive effect on I/R injury by improving hemodynamic function and reducing infarct size compared to the vehicle control group. Moreover, administration of gemigliptin (0.03% and 0.15%) powder in food for 4 weeks reversed hypertrophy and improved diastolic function in spontaneously hypertensive rats. We report here a novel effect of the gemigliptin on I/R injury and hypertension.

Antitumor profiles and cardiac electrophysiological effects of aurora kinase inhibitor ZM447439

Aurora kinases inhibitors, including ZM447439 (ZM), which suppress cell division, have attracted a great deal of attention as potential novel anti-cancer drugs. Several recent studies have confirmed the anti-cancer effects of ZM in various cancer cell lines. However, there have been no studies regarding the cardiac safety of this agent. We performed several cytotoxicity, invasion and migration assays to examine the anti-cancer effects of ZM. To evaluate the potential effects of ZM on cardiac repolarisation, whole-cell patch-clamp experiments were performed with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and cells with heterogeneous cardiac ion channel expression. We also conducted a contractility assay with rat ventricular myocytes to determine the effects of ZM on myocardial contraction and/or relaxation. In tests to determine in vitro efficacy, ZM inhibited the proliferation of A549, H1299 (lung cancer), MCF-7 (breast cancer) and HepG2 (hepatoma) cell lines with IC₅₀ in the submicromolar range, and attenuated the invasive and metastatic capacity of A549 cells. In cardiac toxicity testing, ZM did not significantly affect I(Na), I(Ks) or I(K1), but decreased I(hERG) in a dose-dependent manner (IC₅₀: 6.53 µM). In action potential (AP) assay using hiPSC-CMs, ZM did not induce any changes in AP parameters up to 3 µM, but it at 10 µM induced prolongation of AP duration. In summary, ZM showed potent broad-spectrum anti-tumor activity, but relatively low levels of cardiac side effects compared to the effective doses to tumor. Therefore, ZM has a potential to be a candidate as an anti-cancer with low cardiac toxicity.

Comparison of electrophysiological effects of calcium channel blockers on cardiac repolarization

Dihydropyridine (DHP) calcium channel blockers (CCBs) have been widely used to treat of several cardiovascular diseases. An excessive shortening of action potential duration (APD) due to the reduction of Ca2+ channel current (I(Ca)) might increase the risk of arrhythmia. In this study we investigated the electrophysiological effects of nicardipine (NIC), isradipine (ISR), and amlodipine (AML) on the cardiac APD in rabbit Purkinje fibers, voltage-gated K+ channel currents (I(Kr), I(Ks)) and voltage-gated Na+ channel current (I(Na)). The concentration-dependent inhibition of Ca2+ channel currents (I(Ca)) was examined in rat cardiomyocytes; these CCBs have similar potency on I(Ca) channel blocking with IC50 (the half-maximum inhibiting concentration) values of 0.142, 0.229, and 0.227 nM on NIC, ISR, and AML, respectively. However, ISR shortened both APD50 and APD90 already at 1 microM whereas NIC and AML shortened APD50 but not APD90 up to 30 microM. According to ion channel studies, NIC and AML concentration-dependently inhibited I(Kr) and I(Ks) while ISR had only partial inhibitory effects (<50% at 30 microM). Inhibition of I(Na) was similarly observed in the three CCBs. Since the I(Kr) and I(Ks) mainly contribute to cardiac repolarization, their inhibition by NIC and AML could compensate for the AP shortening effects due to the block of I(Ca).

Wide Spectrum of Inhibitory Effects of Sertraline on Cardiac Ion Channels

Sertraline is a commonly used antidepressant of the selective serotonin reuptake inhibitors (SSRIs) class. In these experiments, we have used the whole cell patch clamp technique to examine the effects of sertraline on the major cardiac ion channels expressed in HEK293 cells and the native voltage-gated Ca2+ channels in rat ventricular myocytes. According to the results, sertraline is a potent blocker of cardiac K+ channels, such as hERG, IKs and IK1. The rank order of inhibitory potency was hERG >IK1> IKs with IC50 values of 0.7, 10.5, and 15.2 microM, respectively. In addition to K+ channels, sertraline also inhibited INa and ICa, and the IC50 values are 6.1 and 2.6 microM, respectively. Modification of these ion channels by sertraline could induce changes of the cardiac action potential duration and QT interval, and might result in cardiac arrhythmia.

Early Results of Subcutaneous Mastectomy with Immediate Breast Reconstruction as a Treatment for Early Breast Cancer

PURPOSE: Subcutaneous mastectomy, combined with immediate breast reconstruction has become popular for breast cancer management. This type of surgery allows for an improved cosmetic result. Although subcutaneous mastectomy is becoming more common, there is little data regarding the local recurrence (LR) rate after this procedure. METHODS: A total of 93 patients were treated for breast cancer by subcutaneous mastectomy with immediate breast reconstruction using permanent prosthesis at Yeungnam University Hospital from September 1996 to April 2003. The inclusion criteria for this procedure were peripherally located tumor, a tumor size smaller than T2, clinically negative axillary lymph node, and a grossly normal nipple and areolar area. To avoid recurrence at the nipple-areolar complex (NAC), a frozen biopsy of the NAC resection margin was performed in all cases. RESULTS: The mean follow-up period was 26 months, and the mean age of the patients was 40.2 years. According to the American Joint Committee on Cancer staging, the stage was as follows: stage 0, 9 patients; stage I, 39 patients; and stage II, 45 patients. The overall LR rate was 5.4% (5 of 93 patients). The mean local relapse-free interval was 30 months. The sites of LR were at the peripheral breast tissue and at the NAC. Only one of 79 patients with preservation of the NAC developed LR at the NAC during the follow-up. LR at the NAC was low as 1.3%. No statistical differences in the LR rates were demonstrated between the NAC-spared group and the NAC-resected group (P>0.05). CONCLUSION: Subcutaneous mastectomy with immediate breast reconstruction using permanent prosthesis as a treatment for early breast cancer is a good treatment modality. Furthermore, preservation of the nipple-areolar complex increases the satisfaction of patients by improving the cosmetic result, and this procedure is both feasible and oncologically safe for breast cancer patients.

The Association between Bone Density at Os Calcis and Body Composition in Healthy Children Aged 9-12 Years / 예방의학회지

OBJECTIVE: This cross-sectional study aimed to quantify the relationship between the bone mineral density at the os calcis and the body mass composition in healthy children. METHODS: The areal bone mineral density was measured at the os calcis with peripheral dual energy X-ray absorptiometry. The fat free mass, fat mass and percentage fat mass were measured using bioelectric impedance, in 237 Korean children, aged 9 to 12 years. The sexual maturity was determined by self assessment, using standardized series of the 5 Tanner stage drawings, accompanied by explanatory text. RESULTS: From multiple linear regression models, adjusted for age, sexual maturity and height, the fat free mass was found to be the best predictor of the calcaneal bone mineral density in both sexes. About 15 and 20% variabilities were found in the calcaneal bone mineral densities of the boys and girls, respectively, which can be explained by the fat free mass. After weight adjustment, the percentage fat mass was negatively associated with the calcaneal bone mineral density in both sexes. CONCLUSIONS: The findings of this study suggest that the fat free mass, among the body compositions, is the major determinant of bone mineral density at the os calcis in Korean children aged 9 to 12 years. Obesity, defined as the percentage fat mass, is assumed to have a negative effect on the calcaneal bone density in children of the same weight.

Expression of Estrogen Receptor-beta and Its Variants in Normal Mammary and Tumor Tissues / 한국유방암학회지

PURPOSE: Since the discovery of estrogen receptor-beta(ER-beta, five C-terminal variants of ER-beta were identified. We designed this study to investigate the pattern and clinical implications of ER-betaand its splicing variants expression in normal and malignant mammary tissues. METHODS: Using reverse transcription polymerase chain reaction (RT-PCR), we examined the expression levels of ER-alpha and ER-betaand its five splicing variants (beta1, beta2, beta3, beta4, beta5) in 50 paired normal and cancer tissues. We measured the densities of RT-PCR products using Tina version 2.10 (Raytest, Germany). Firstly, the incidence and intensity of ER-alpha and ER-beta and its five splicing variants were compared. Then the expression of ER-betamRNA splicing variants was also analyzed with regard to the ER-alphaprotein expression measured by immuno-histochemical staining and the menopausal status of the patients. Chi-square test and paired samples t-test were used for statistical analysis. Differences were considered to be significant with a p-value of less than 0.05. RESULTS: The expression of ER-betamRNA variants in normal breast and cancer tissues were as follows: ER-beta2 (100%/100%), ER-beta4 (76%/74%), ER-beta5 (32%/58%), and ER-beta1 (14%/16%). ER-beta3 was not detected at all. In terms of intensity, we observed a significant decrease of ER-beta2 (P<0.001) and an increase of ER-beta5 (P=0.004) in the mRNA expression levels among breast cancers compared to the corresponding normal breast tissues. Compared to the corresponding normal tissues, a significant decrease of ER-beta2 in cancer tissues was observed in patients with ER-alpha-positive (P<0.001), with age over 50 (P=0.01), and under 50 (P=0.04) as well, but not in patients with ER-alpha-negative (P=0.48). ER-beta4 also significantly decreased in patients with ER-alpha-positive (P=0.004) and with age over 50 (P=0.07). ER-beta5 showed a significant increment only in patient aged over 50 (P=0.04). CONCLUSION: ER-alpha mRNA expression significantly increases but ER-beta mRNA expression decreases in the cancer tissues compared to the corresponding normal tissues. Among ER-beta variant forms, ER-beta2 is predominant in both normal and malignant mammary tissues and ER-beta4, ER-beta5, and ER-beta1 in descending order but ER-beta3 does not express in mammary tissues. The decrease of ER-beta2 and ER-beta4 expression is prominent in cancer tissue especially in ER-alpha-positive cancers, which suggests that ER-beta2 and ER-beta4 may possess a regulatory function in mammary carcinogenesis. Further investigations to verify the roles of ER-beta variants are mandatory.

The Association between Bone Density at Os calcis and Body Composition according to Years since Menopause in Postmenopausal Women Aged 45-84 Years Living in a Rural Area / 한국역학회지

OBJECTIVES: This cross-sectional study aimed to compare early postmenopausal women with late menopausal women in respect to body composition as a major determinant of calcaneal bone density. METHODS: Areal bone density was measured at os calcis with peripheral dual energy X-ray absorptiometry. Soft lean mass and fat mass were measured using bioelectric impedance in 109 postmenopausal women aged 45 to 84 years. RESULTS: When age and height were adjusted, the variance of calcaneal bone density was better explained by fat mass (15%) than by soft lean mass (7%) in early postmenopausal women. In contrast, soft lean mass (17%) explained the variance of calcaneal bone density better than fat mass (11%) in late postmenopausal women. However, interaction terms between years since menopause (YSM) and soft lean mass or fat mass were not statistically significant in multiple linear regression model for total postmenopausal subject. CONCLUSION: The findings of this study suggest that fat mass is the major determinant of calcaneal bone density in early postmenopausal women, whereas fat free mass is more important determinant of calcaneal bone density in late postmenopausal women.

Mitogen-activated Protein Kinases Activities and c-erbB-2 Expression in Breast Cancer Carcinogenesis and Progression

PURPOSE: Increased level mitogen-activated protein kinase (MAPK) and activation of MAPK have been reported in human breast cancers, especially in breast cancers with HER2/neu overexpression. To understand the relationship between the MAPK protein expressions and other clinico-pathological parameters, we examined the status of MAPKs in 20 breast cancers compared to those of paired normals. METHODS: A total of 20 breast cancers and paired normal breast tissues were included in this study. Tissues were obtained at the operation room and stored at -80degrees C. Tissue proteins were extracted and the concentration was determined by Bio-Rad protein assay method. Western blot analysis were performed to determine the level of MAPKs expressions using 100 ug of tissue protein in 8%, 10%, or 12% sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE). MAPK assays were carried out by a non-radioactive method developed by Cell Signaling Tech. as recommened by the manufacturer. Clinico-pathological information was provided from the Breast Cancer Registry of Department of Surgery, Yonsei University College of Medicine. RESULTS: The levels of MAPKs were higher in 95% of breast cancers compared to those of paired normals. The levels of ERK1/2 were significantly higher in cancer tissues compared to paired normals but the activated forms were not. The levels of JNK, p38, and MKP1 proteins were significantly increased in the cancer tissue compared to the paired normals. The levels of ERK1/2 and activated ERK1/2 proteins were not different between tumor stages. There were no significant differences of the levels of ERK1/2 and activated ERK1/2 proteins between HER2-negative and HER2- positive cancers. There were significantly higher levels of activated ERK1/2 proteins in ER-positive cancers than those in ER-negative cancers (P<0.05). CONCLUSION: The levels of MAPKs, but not the activated forms, seem to be increased in breast cancer tissues compared to those of paired normals. The levels of activated MAPKs seem to be associated with estrogen receptor expression in cancer tissues.

Expression of Estrogen Receptor-beta mRNA in Various Mammary Tissues / 한국유방암학회지

PURPOSE: Estrogen signal transduction plays very important roles in both normal mammary development and neoplastic progression. Since the discovery of estrogen receptor-beta (ER-beta) there have been many controversial reports on the role of ER-beta in breast carcinogenesis and progression, and prognostic implications. ER-beta mRNA levels were investigated in various mammary tissues in order to verify the role of ER-beta expression in breast carcinogenesis. METHODS: Using messenger RNA (mRNA) in situ hybridization, we examined ER-beta expression in 60 paired normal and cancer tissues, 11 paired normal and benign breast tumor tissues, and 10 metastatic lymph nodes. We determined the intensity and extent (proportion of cells with positive hybridization) of the mRNA hybridization signals and gave scores 0 to 3; no hybridization (0), minimal (1), moderate (2), and strong (3) by the hybridization intensity and no hybridization (0), hybridization in less than 10% of cells (1), 10~50% (2), and more than 50% of cells (3) by the proportion of positively hybridized cells. Chi-square test, independent t-test or one-way ANOVA test was used for the statistical analysis and differences were considered to be significant with a p-value of less than 0.05. RESULTS: There was no statistically difference in ER-beta expression between normal and benign mammary tissues. ERbeta expression was significantly decreased in breast cancer and metastatic lymph node tissues compared with normal mammary and benign breast tumor tissues (P<0.01). The intensity and extent of ER beta expression were also significantly lower in breast cancer and metastatic lymph node tissues than in the normal mammary and benign breast tumor tissues (P<0.01). In cases of positive hybridization, the sum of scores of intensity and area were also significantly higher in normal and fibroadenoma tissues than in cancer or metastatic lymph nodes (P<0.01). CONCLUSION: ER beta transcription decreases in the process of breast cancer development, which suggests a protective role of ER beta in breast carcinogenesis.

Anti-HER2/neu Peptide Producing Vector System for Biologic Therapy - Is It Possible to Mass-produce the Peptide?

A humanized monoclonal antibody against HER2 has been using in a clinical setting and has been shown to possess therapeutic properties. A mimetic peptide against HER2 was also reported to bind to the HER2 receptor with some therapeutic potential. Based on a previous report and the sequence of Herceptin, we designed oligonucleotides of anti-HER2 mimetic peptides, named V2 and V3 peptides, in order to develop a peptide- producing vector system for biologic therapy against HER2- overexpressing cancers. We also adopted the sequence of a previously reported mimetic peptide, V1 (Park BW et al. Nat. Biotechnol, 2000, 18: 194-198), as a reference peptide. We examined the effects of the V2 and V3 peptides against the HER2-overexpressing cell lines, SK-BR-3 and T6-17. Transient transfection of the construct expressing V1 and V2 inhibited cell proliferation in HER2-overexpressing cell lines by 20 - 30%, but had no effect on the HER2-negative NIH3T3 cells. The proliferation inhibition shown by V2 was slightly better than that shown by V1. Recombinant peptides V2 and V3 were produced on a large scale in an E. coli system, and the V2 peptide showed anti-HER2-specific tumor cell proliferation inhibition of 10% to 30%. Current results suggest that anti-HER2 mimetic peptides, overexpressed by a constitutive promoter or produced in an E. coli system, could specifically inhibit the proliferation of HER2-expressing cancer cells. Further efforts to augment the biologic specificity and efficacy and to develop new technologies for the purification of the peptide from the E coli system are needed.

Gallbladder Agenesis / 한국간담췌외과학회지

Gallbladder agenesis is a rare condition of hepatobiliary congenital anomaly. It is caused by failure of development of the caudal division of the primitive hepatic diverticulum or failure of vacuolization after the solid phase of embryonic development. It is divided into 2 groups: (1) those whose conditions are discovered clinically because of persistent symptoms and proven by abdominal exploration with operative cholangiography; and (2) those who are asymptomatic during life and whose conditions are discovered only at necropsy. If symptoms are present, they are unlikely to be related to gallbladder disease. It is impossible, at present, to make a preoperative diagnosis of gallbladder agenesis. Operative cholangiography is absolutely necessary to rule out an intrahepatic gall bladder. Confirmation at surgery and autopsy requires thorough dissection of the biliary tract and liver bed. Therefore, we presented this case with a brief review of the related literature.

Sister chromatid exchange induced by diethylstilbestrol in lymphocytes from pregnant, premenopausal & postmenopausal women / 대한산부인과학회잡지

No abstract available.